The purpose of this application is to test a new model for the physiology of energy homeostasis. We hypothesize that hormones that circulate at concentrations proportional to body fat content, such as insulin and leptin, reduce food intake and body weight by acting upon discrete hypothalamic signaling systems referred to as central effector pathways. The combined actions of insulin and leptin in the hypothalamus are proposed in turn to potentiate the response of brainstem to afferent, meal-satiety signals such as cholecystokinin (CCK) that lead to the termination of single meals. Though this mechanism, the amount of consumed during individual meals is proposed to decrease when hypothalamic leptin (or insulin) signaling is increased, leading to weight loss. Conversely, the effect of a sustained energy deficit to deplete body fat stores is hypothesized to reduce hypothalamic leptin signaling and thereby increase meal size, since animals become relatively insensitive to signals that terminate the meal. The first major objective of this application is to clarify the interactions between insulin and leptin in the control of food intake and hypothalamic neuropeptide gene expression. This will be accomplished by 1) determining if brain responsiveness to insulin can be restored in leptin-deficient ob/ob mice by infusing leptin systemically at a low dose, and 2) by determining if the effect of leptin to lower circulating insulin levels limits its ability to reduce food intake. The second major objective is to investigate the effect of leptin on the satiety and brainstem response to CCK. Studies will investigate 1) if reduced CCK responsiveness induced by fasting or genetic leptin deficiency is reversed by site or both; and 3) if central effector peptides that are regulated by leptin act in the hypothalamus to modulate the brainstem and feeding responses to CCK. By improving our understanding of the integration of long and short-term regulators of energy intake, these studies will help to identify sites for therapeutic intervention in the treatment of obesity and other weight disorders.